Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice
The sympathetic nervous system is a major efferent pathway through which the central nervous system controls the function of peripheral organs. Genetic and pharmacologic evidence in mice indicated that stimulation of the β2 adrenergic receptor (β2AR) in osteoblasts promotes bone loss, leading to the...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | Bone Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352187218300561 |
| _version_ | 1818847498996809728 |
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| author | Yuantee Zhu Yun Ma Florent Elefteriou |
| author_facet | Yuantee Zhu Yun Ma Florent Elefteriou |
| author_sort | Yuantee Zhu |
| collection | DOAJ |
| description | The sympathetic nervous system is a major efferent pathway through which the central nervous system controls the function of peripheral organs. Genetic and pharmacologic evidence in mice indicated that stimulation of the β2 adrenergic receptor (β2AR) in osteoblasts promotes bone loss, leading to the paradigm that high sympathetic nervous activity is deleterious to bone mass. However, considerably less data exist to understand the putative impact of endogenous norepinephrine (NE), released by sympathetic nerves, on bone homeostasis. In this study, we investigated the in vivo expression and activity of the norepinephrine transporter (NET), a membrane pump known to actively uptake NE from the extracellular space in presynaptic neurons. Consistent with previously published in vitro data showing NET uptake activity in differentiated osteoblasts, we were able to detect active NET-specific NE uptake in the mouse cortical bone compartment in vivo. This uptake was the highest in young mice and accordingly with an age-related reduction in NET uptake, NE bone content increased whereas Net RNA and protein expression decreased with age. Histologically, NET expression in adult mouse bones was detected in osteocytes via immunofluorescence. Lastly, taking advantage of tissue-specific fluorescent reporter mice, we used CLARITY imaging and light sheet microscopy to visualize the 3D distribution of sympathetic fibers in whole mount preparations of bone tissues. These analyses allowed us to detect tyrosine hydroxylase (TH)-positive sympathetic nerve fibers penetrating the cortical bone, where NET+ osteocytes reside. Together, these in vitro results support the existence of an age-dependent extraneuronal and osteocytic function of NET with potential to buffer the bone catabolic action of endogenous NE released by sympathetic nerves in vivo. Keywords: Sympathetic nerves, Bone remodeling, Norepinephrine, Transporter, Uptake, Osteocyte, Tracing, Imaging, Aging |
| first_indexed | 2024-12-19T06:02:25Z |
| format | Article |
| id | doaj.art-0cab191923d646798e35f4d7c30fb4cd |
| institution | Directory Open Access Journal |
| issn | 2352-1872 |
| language | English |
| last_indexed | 2024-12-19T06:02:25Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Bone Reports |
| spelling | doaj.art-0cab191923d646798e35f4d7c30fb4cd2022-12-21T20:33:15ZengElsevierBone Reports2352-18722018-12-019188198Cortical bone is an extraneuronal site of norepinephrine uptake in adult miceYuantee Zhu0Yun Ma1Florent Elefteriou2Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, United States; Department of Orthopedics, Baylor College of Medicine, Houston, TX, United StatesDepartment of Orthopedics, Baylor College of Medicine, Houston, TX, United StatesDepartment of Orthopedics, Baylor College of Medicine, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States; Corresponding author at: Departments of Molecular and Human Genetics, Department of Orthopedic Surgery at Baylor College of Medicine, Houston, TX, United States.The sympathetic nervous system is a major efferent pathway through which the central nervous system controls the function of peripheral organs. Genetic and pharmacologic evidence in mice indicated that stimulation of the β2 adrenergic receptor (β2AR) in osteoblasts promotes bone loss, leading to the paradigm that high sympathetic nervous activity is deleterious to bone mass. However, considerably less data exist to understand the putative impact of endogenous norepinephrine (NE), released by sympathetic nerves, on bone homeostasis. In this study, we investigated the in vivo expression and activity of the norepinephrine transporter (NET), a membrane pump known to actively uptake NE from the extracellular space in presynaptic neurons. Consistent with previously published in vitro data showing NET uptake activity in differentiated osteoblasts, we were able to detect active NET-specific NE uptake in the mouse cortical bone compartment in vivo. This uptake was the highest in young mice and accordingly with an age-related reduction in NET uptake, NE bone content increased whereas Net RNA and protein expression decreased with age. Histologically, NET expression in adult mouse bones was detected in osteocytes via immunofluorescence. Lastly, taking advantage of tissue-specific fluorescent reporter mice, we used CLARITY imaging and light sheet microscopy to visualize the 3D distribution of sympathetic fibers in whole mount preparations of bone tissues. These analyses allowed us to detect tyrosine hydroxylase (TH)-positive sympathetic nerve fibers penetrating the cortical bone, where NET+ osteocytes reside. Together, these in vitro results support the existence of an age-dependent extraneuronal and osteocytic function of NET with potential to buffer the bone catabolic action of endogenous NE released by sympathetic nerves in vivo. Keywords: Sympathetic nerves, Bone remodeling, Norepinephrine, Transporter, Uptake, Osteocyte, Tracing, Imaging, Aginghttp://www.sciencedirect.com/science/article/pii/S2352187218300561 |
| spellingShingle | Yuantee Zhu Yun Ma Florent Elefteriou Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice Bone Reports |
| title | Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice |
| title_full | Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice |
| title_fullStr | Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice |
| title_full_unstemmed | Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice |
| title_short | Cortical bone is an extraneuronal site of norepinephrine uptake in adult mice |
| title_sort | cortical bone is an extraneuronal site of norepinephrine uptake in adult mice |
| url | http://www.sciencedirect.com/science/article/pii/S2352187218300561 |
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